19-55948229-C-G

Position:

• chr19-55948229-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_176811.2(NLRP8):​c.327C>G​(p.Asn109Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NLRP8 NM_176811.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.244

Genes affected

NLRP8 (HGNC:22940): (NLR family pyrin domain containing 8) This gene encodes a member of the nucleotide-binding oligomerization domain/ leucine rich repeat/ pyrin domain containing (NLRP) subfamily, which belongs to the Nod-like receptor family of proteins. NLRP genes play roles in the mammalian innate immune system through inflammasome formation and activation of caspases. In addition, NLRP genes have been found to function during mammalian reproduction. Consistent with a function during human preimplantation development, this gene is expressed at high levels in oocytes with decreased levels in embryos. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26902753).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NLRP8	NM_176811.2	c.327C>G	p.Asn109Lys	missense_variant	1/10	ENST00000291971.7	NP_789781.2
NLRP8	NM_001317000.1	c.327C>G	p.Asn109Lys	missense_variant	1/10		NP_001303929.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NLRP8	ENST00000291971.7	c.327C>G	p.Asn109Lys	missense_variant	1/10	1	NM_176811.2	ENSP00000291971.3
NLRP8	ENST00000590542.1	c.327C>G	p.Asn109Lys	missense_variant	1/10	1		ENSP00000468121.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 58

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 02, 2024

The c.327C>G (p.N109K) alteration is located in exon 1 (coding exon 1) of the NLRP8 gene. This alteration results from a C to G substitution at nucleotide position 327, causing the asparagine (N) at amino acid position 109 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	11
DANN	Benign	0.88
DEOGEN2	Benign	0.021	T;.
Eigen	Benign	-0.93
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0087	N
LIST_S2	Benign	0.29	T;T
M_CAP	Benign	0.0079	T
MetaRNN	Benign	0.27	T;T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	1.2	L;L
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-4.2	D;.
REVEL	Benign	0.15
Sift	Benign	0.078	T;.
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.99	D;D
Vest4		0.21
MutPred		0.68		Gain of methylation at N109 (P = 0.0216);Gain of methylation at N109 (P = 0.0216);
MVP		0.27
MPC		0.39
ClinPred		0.34	T
GERP RS		-4.5
Varity_R		0.15
gMVP		0.16

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-56459595;